tbuckley/cabot-search huggingface dataset:
Abstract 3810: MicroRNA-483-5p inhibits cell steatosis and fibrosis by targeting PPARa, TIMP2 and HCC cell proliferation by modulating notch signaling
Authors: Suryakant Niture, Sashi Gadi, Qi Qi, Maxwell Gyamfi, Leslimar Rios-Colon, Rency Varghese, Habtom Ressom, Deepak Kumar
Journal: Cancer Research (2023)

Abstract MicroRNAs (miRNAs) are small non-coding RNA molecules that bind with 3’ untranslated regions (UTRs) of genes and regulate expression. Downregulation of miR-483-5p (miR-483), is associated with the progression of hepatocellular carcinoma (HCC). However, the molecular and mechanistic role of miR-483 in nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver diseases (AFLD), and HCC remain elusive. In the current study, we investigated the biological significance of miR-483-5p in NAFLD, AFLD, and HCC in vitro and in vivo. Our data show that the expression of miR-483 was downregulated in tumor samples from HCC patients. Overexpression of miR-483 in HCC cells dysregulated Notch signaling, inhibited cell proliferation/migration, induced apoptosis, and increased sensitivity towards sorafenib/regorafenib; anti-HCC drugs. Interestingly, miR-483 overexpression downregulated cell steatosis and fibrogenic signaling in HCC cells. Mechanistically, miR-483 targets peroxisome proliferator-activated receptor α (PPARα) and tissue inhibitor of metalloproteinases 2 (TIMP2) gene expression by binding to 3’-UTR and suppress cell steatosis and fibrosis. Down-regulation of miR-483 was observed in mice fed with a high-fat diet (HFD) or alcohol which lead to increased hepatic steatosis/fibrosis. Our data suggest that miR-483 inhibits cell steatosis and fibrogenic signaling, and functions as a tumor suppressor in HCC. Therefore, miR-483 may be used as a novel therapeutic target for NAFLD/AFLD/HCC management in patients with fatty live diseases/HCC. Citation Format: Suryakant Niture, Sashi Gadi, Qi Qi, Maxwell Gyamfi, Leslimar Rios-Colon, Rency Varghese, Habtom Ressom, Deepak Kumar. MicroRNA-483-5p inhibits cell steatosis and fibrosis by targeting PPARa, TIMP2 and HCC cell proliferation by modulating notch signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3810.
Abstract 1699: Targeting mercapturic acid pathway transporter in chemoradiotherapy resistant ovarian cancer
Authors: Sharad S. Singhal, Er Yue, Prakash Kulkarni, David Horne, Sanjay Awasthi, Edward Wang, Ravi Salgia
Journal: Cancer Research (2023)

Abstract Ovarian cancer is the most common and the most lethal malignancies arising in the female reproductive system. Morbidity and mortality associated with ovarian cancer will continue to impact the female population. Although cisplatin centered chemotherapy is the first line anticancer agent for human ovarian cancer, chemoresistance and adverse side effects remain major hurdles to successful treatment. The effective targets for cancer therapy must be desirably expressed differentially in particular cancers as compared with normal cells. Also, there should be an essential dependence of cancer cells on the target compared to non malignant cells. Ideally, the target should be understood in the context of existing biochemical and signaling frameworks known to play a direct role in a particular carcinogenesis or in regulating the response to therapy. In the context of striking chemo radiotherapy resistance of ovarian cancer and the fundamental role of RLIP as an important mercapturic acid pathway transporter that is essential for survival and therapy resistance in cancers, we investigated the role of RLIP in regulating the critical signaling proteins involved in relaying the inputs from multiple upstream survival pathways and mechanisms contributing to chemo radiotherapy resistance in ovarian cancer. Compounds that inhibit, deplete, or downregulate RLIP will function as wide spectrum agents to treat ovarian cancer, independent of common signaling pathway mutations. Here, we demonstrate that RLIP expression is significantly greater in ovarian cancer cells than in non malignant cells, and RLIP is an essential requirement for cancer formation, and its depletion or inhibition will prevent ovarian carcinogenesis as well as metastases. Taken together, the results of our studies provided insights into a novel anticancer effect of RLIP depletion/inhibition on ovarian cancer and might open new therapeutic avenues for the treatment of ovarian cancer. Supported in part by the Department of Defense grant W81XWH 22 1 0331. Funding from the Beckman Research Institute of City of Hope is also acknowledged. Citation Format: Sharad S. Singhal, Er Yue, Prakash Kulkarni, David Horne, Sanjay Awasthi, Edward Wang, Ravi Salgia. Targeting mercapturic acid pathway transporter in chemoradiotherapy resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1699.
Abstract 1331: A novel approach to treating hormonal breast cancer using clinical database and 3D ex vivo model
Authors: Chaeun (Christine) Song, SeungBaek Lee
Journal: Cancer Research (2023)

Abstract Type 2 diabetes (T2D) female patients have a higher risk of being diagnosed and have worse survival for breast cancer compared to non-diabetic females. Although the relationship between these two female diseases has been reported, specific functional studies on which subtypes of breast cancer are affected and which genes are regulated by T2D are little known. Here, I found that Forkhead Box A1 (FOXA1) and Metformin, anti-diabetic medication for T2D, affect hormonal positive (HR+) breast cancer tumor cell growth and metastasis. 14 diabetes-related genes highly expressed in three HR+ breast cancer cell lines but not other breast cancer subtypes using a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4,032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Specifically, the high expression of FOXA1 correlated to a worse ER+/PR+ breast cancer patient survival rate. Consistent with this, the loss of FOXA1 inhibited the tumor proliferation and invasion of MCF-7 and T47D HR+ breast cancer cell lines using in vitro. Metformin (1,1-dimethylbiguanide hydrochloride) conspicuously inhibits the tumor cell growth in MCF-7 human hormonal breast cancer cells. Metformin or FOXA1 deletion enhanced Tamoxifen-mediated tumor growth inhibition in HR+ breast cancer cell lines through the ex vivo three-dimensional (3D) organoid model. Therefore, HR+ breast cancer is closely related to T2D, and metformin and FOXA1 inhibition might be an optimal new treatment for patients with HR+ breast cancer when combined with tamoxifen, a hormone therapy. Citation Format: Chaeun (Christine) Song, SeungBaek Lee. A novel approach to treating hormonal breast cancer using clinical database and 3D ex vivo model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1331.
Abstract 1694: Loss of<i>ZNF251</i>stimulates NHEJ resulting in PARP inhibitor resistance in<i>BRCA1</i>-mutated cancer cells
Authors: Jian Huang, Tomasz Skorski
Journal: Cancer Research (2023)

Abstract The poly (ADP-ribose) polymerases (PARPs) inhibitors are an exciting new class of agents that have shown efficacy in treating various cancers, especially those harboring BRCA1/2 mutations. The cancer associated BRCA1/2mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPi) have been applied to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting the accumulation of toxic DSBs. Unfortunately, PARPi resistance is common and develops through multiple mechanisms. Restoring HR and/or stabilizing replication forks are two major mechanisms of PARPi resistance in BRCA1/2-mutated cells. To further understand the mechanisms of drug resistance to PARPi, we took an unbiased approach with a CRISPR-pooled genome-wide library to screen new genes whose loss-of-function confers resistance to PARPi olaparib. We identified ZNF251, a transcription factor, and found that its loss-of-function led to the PARPi resistance in multipleBRCA1-mutated breast and ovarian cancer lines. Elevated activities of both HR and non-homologous end joining (NHEJ) repair were detected in cancer cells harboring BRCA1 mutation and ZNF251 deletion (BRCA1mut+ZNF251del) and were associated with enhanced expression of RAD51 and Ku70/Ku80, respectively. Furthermore, we showed that a DNA-PKcs inhibitor restored sensitivity of BRCA1mut+ZNF251del cells to PARPi ex vivo and in vivo. Taken together, our study discovered a novel gene ZNF251 whose loss-of-function conferred resistance to PARPi in BRCA1-mutated breast and ovarian cancers and identified DNA repair pathway responsible for this effect. Citation Format: Jian Huang, Tomasz Skorski. Loss ofZNF251stimulates NHEJ resulting in PARP inhibitor resistance inBRCA1-mutated cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1694.
Abstract 4627: Immune profiling of immunotherapy and adjuvant chemotherapy pretreatment NSCLC tissues by CODEX
Authors: James Monkman, Afshin Moradi, Connor O'Leary, Zhenqin Wu, Steven Hamel, David Mason, Fabian Schneider, James Robert Mansfield, Aaron Meyer, Ken O'Byrne, Arutha Kulasinghe
Journal: Cancer Research (2023)

Abstract Non-small cell lung cancer (NSCLC), including adenocarcinoma and squamous cell carcinoma subtypes, is a leading cause of cancer deaths worldwide. Treatment of NSCLC has advanced from chemotherapy modalities to the use of immunotherapy, namely immune checkpoint inhibitors (ICIs) which enhance the adaptive immune response against tumour cells. Thus, while the immune cell composition of tumours and its influence on treatment outcomes is poorly understood, it likely holds the key to effective, personalized treatment regimens. Here we profiled an adjuvant chemotherapy (n=61) as well as a second line immunotherapy (n=42) NSCLC cohort by the Phenocycler CODEX technology (highplex spatial proteomics) to investigate the association between immune composition and patient outcome. We applied a panel of 38 markers to delineate naïve, memory, cytotoxic and hyperactivated T cell states, as well as B cells, Tregs and myeloid lineage innate immune cell types. Our study sought to understand the heterogeneity of tumour-immune composition across patients and investigate the spatial neighbourhoods and clusters that these cells inhabit within TMA cores. We used Phenoplex™ software for tissue segmentation (into classes for tumor, stroma, artifacts, blood vessels, etc.), cellular segmentation, and cellular phenotyping based on thresholds for each marker, and then performed spatial analyses (distances, interactions, neighborhoods) using SpatialMap1 to identify cellular motifs associated with clinical phenotypes. Our study has identified spatial features associated with immune contexture linked to therapy outcome in both chemotherapy and immunotherapy modalities. Taken together, our study demonstrates the utility of spatial proteomics to identify cellular features associated with outcome to therapy in lung cancer. 1) Trevino A, Ivison G, Hamel S, Chiou A (2022). SpatialMap: Analysis of Spatial Biology Data. R package version 0.4.57. Citation Format: James Monkman, Afshin Moradi, Connor O'Leary, Zhenqin Wu, Steven Hamel, David Mason, Fabian Schneider, James Robert Mansfield, Aaron Meyer, Ken O'Byrne, Arutha Kulasinghe. Immune profiling of immunotherapy and adjuvant chemotherapy pretreatment NSCLC tissues by CODEX. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4627.
Abstract 5288: Single-cell multiomics reveal divergent transcriptional and epigenetic cell states in breast cancer
Authors: Aysegul Ors, Hisham Mohammed, Aaron R. Doe, Syber Haverlack, Mithila Handu, Ryan Mulqueen
Journal: Cancer Research (2023)

Abstract Over the recent years, single-cell sequencing studies have been used to better describe the highly heterogeneous nature of breast cancers on transcriptional and genetic levels. It is also known that breast cancers are highly driven by estrogen receptor alpha (ER), a transcription factor that’s important for mammary tissue homeostasis. However, little is known about how estrogen signaling heterogeneity affects cancer progression and response to anti-estrogen therapy at a single-cell level. Leveraging single-omic and multi-omic single-cell sequencing technologies, we tracked estrogen response in breast cancer cell and organoid models. We developed TITAN, a topic-modeling based analysis tool to reveal signaling gradients in single-cell RNA-seq data. With this approach we showed that distinct cells prioritize distinct gene groups in response to estrogen. We defined two of these gene networks to be driven by either ER or FOXM1. These same networks exist not only in all the models used in the study but also in breast cancer patient datasets. FOXM1 is activated in estrogen treated cells and the FOXM1 driven gene signature correlates with more aggressive types of disease. Our combined scRNA and scATAC-seq experiments also highlighted distinct chromatin accessibility states associated with either cell group. Using scNMT-seq in patient samples we were able to describe DNA methylation and chromatin accessibility influence on hormone signaling patterns at the single-cell level. Together, our results provide insights into defining transcriptional and epigenetic cell states in ER positive breast cancer. Citation Format: Aysegul Ors, Hisham Mohammed, Aaron R. Doe, Syber Haverlack, Mithila Handu, Ryan Mulqueen. Single-cell multiomics reveal divergent transcriptional and epigenetic cell states in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5288.
Abstract 5283: Glucocorticoid receptor (GR) activity alters invasive lobular breast cancer (ILC) oncogenic properties
Authors: Ishrat Durdana, Candace Frerich, Muriel Laine, Smita Rindhe, Lynda Bennett, Robert Bachoo, Geoffrey Greene, Suzanne Conzen
Journal: Cancer Research (2023)

Abstract Invasive breast cancer (BC) is commonly divided into two subtypes, invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). ILC makes up 10-15% of all BC cases. Expression of nuclear hormone receptors further define clinical histology and directs treatment; receptors include estrogen (ER), progesterone (PR), androgen (AR), and glucocorticoid receptors (GR). Tumor GR expression activation is associated with good prognosis in ER+ but poor prognosis in ER- BC. The majority of ILC tumors are ER+, and we have found that GR expression in primary ILC tumors correlates with improved overall survival. We hypothesized that GR activity in ILC may play a role in ILC’s indolent natural history and could alter its metastatic tendency. We used two isogenic ILC cell lines, each with and without GR expression (MM134-GR+/GR- and SUM44PE-GR+/GR-) to study GR-mediated ILC associated phenotypes. Specifically, we describe GR’s effect on proliferation in vitro and tumor formation in the in vivo MIND model. We also measured GR-mediated ILC adherence to major components of the extra cellular matrix (collagen I, collagen II, laminin, fibronectin, vitronectin, and tenascin). To recapitulate early metastasis, we examined ILC cell movement through a 10 uM microchannel device. We found that GR expression and activation in ILC cell lines cause decreased cell proliferation and decreased adherence to laminin. Preliminary experiments suggest that GR activation altered ILC cell’s ability to enter and navigate through restrictive 10 uM microchannels. Given our preliminary findings, we will investigate the effect of selective GR modulators (SGRMs) on ILC phenotypes and gene expression. We hypothesize that the gene expression changes following GR activation will be different in ILC compared to IDC. In addition, we are examining the genes required for survival of ILC cells on collagen using an in vitro CRISPR-Cas9 screen. In vivo experiments examining the association of GR expression with tumor growth in vivo are ongoing. Citation Format: Ishrat Durdana, Candace Frerich, Muriel Laine, Smita Rindhe, Lynda Bennett, Robert Bachoo, Geoffrey Greene, Suzanne Conzen. Glucocorticoid receptor (GR) activity alters invasive lobular breast cancer (ILC) oncogenic properties. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5283.
Abstract 4167: Translational control of T cell exhaustion in melanoma, perspectives in therapeutics
Authors: Samad Muhammadnejad, Biswendu Biswas, Ramdane Guemiri, Naima Benannoune, Jérémy Lavigne, Virginie Quidville, Jean-Yves Scoazec, Stephan Vagner, Caroline Robert
Journal: Cancer Research (2023)

Abstract Background: Eukaryotic initiation factor 4F (eIF4F) complex plays a pivotal role in the selective translational control of protein expression in cancer. We previously showed that the inhibition of eIF4F had both a direct antitumor effect that could overcome resistance to BRAF inhibition in BRAFV600 melanoma and an indirect immune-mediated antitumor effect via PD-L1 down regulation resulting from STAT1 decreased translation. We now explore further the translational control of immune checkpoints (ICs) on T cell and its link with lymphocyte exhaustion. Methods: We performed polysome profiling (PP) on peripheral blood-derived activated and resting T lymphocytes as well as tumor-infiltrating lymphocytes (TILs) isolated from melanoma specimens in the presence or absence of silvestrol as an eIF4A (the helicase component of eIF4F) inhibitor. We studied the expression of ICs and exhaustion-associated transcription factors on lymphocytes at the various stages of exhaustion. The tumor cell lysing capacity of PBMC was evaluated with and without silvestrol. We also assessed the effect of silvestrol on tumor microenvironment in the BP syngeneic melanoma tumor model. Results: Silvestrol decreased the translation of multiple ICs in activated CD4+ and CD8+ T cells, including TOX, NFAT1, NFAT2, LAG3, and TIM3 (the two latter being also transcriptionally regulated). FACS analysis confirmed the dose-dependent decrease of protein expression of exhaustion-associated transcription factors TOX, NFATc1, TCF1 and T-bet in activated lymphocytes. This effect was more prominent in more exhausted T cells. Silvestrol decreased T cell proliferation but, in co-culture experiments, it increased immune cell killing of melanoma cells by T-lymphocytes. In the BP murine model, the antitumor effect of silvestrol was associated with denser T cell infiltration and less exhausted TILs than control tumors. Conclusion: Our findings demonstrate the role of eIF4F in the orchestrated regulation of functionally related proteins involved in T cell exhaustion. They highlight the drugability of eIF4A for the cancer treatment and suggest that eIF4A inhibitors could be useful with IC inhibitors in combination or sequentially. Citation Format: Samad Muhammadnejad, Biswendu Biswas, Ramdane Guemiri, Naima Benannoune, Jérémy Lavigne, Virginie Quidville, Jean-Yves Scoazec, Stephan Vagner, Caroline Robert. Translational control of T cell exhaustion in melanoma, perspectives in therapeutics. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4167.
Abstract 3209: Metabolic characterization of radiation-induced cardiotoxicity
Authors: Sarah C. Elliott, Jayesh Sharma, Elizabeth R. Zhang-Velten, Abdallah Elnwasany, Chantal Vidal, Luke Szweda, Prasanna Alluri
Journal: Cancer Research (2023)

Abstract Background: Approximately 50% of all cancer patients receive radiation therapy as a component of their cancer care. While radiation therapy has demonstrable benefit in improving survival in patients, radiation-induced heart disease (RIHD) is a major contributor to morbidity and mortality in cancer survivors with history of thoracic radiation. Understanding metabolic changes underlying RIHD may enable development of novel diagnostic and therapeutic approaches for early detection and treatment of RIHD. The high energetic demands of the heart require properly functioning mitochondria to meet the ATP production needs. Fatty acids are the primary metabolic substrates for energy production in a healthy heart. However, under conditions of stress, the cardiac metabolism shifts towards increased glucose utilization. In this study, we characterize the impact of radiation of cardiac substrate utilization and energy production. Methods: Pre-clinical RIHD models were established by administering whole heart radiation (8Gy x 5) in mice and rats followed by structural and biochemical characterization. Transmission electron microscopy and western blot analyses were used to characterize structural and biochemical changes in the heart in response to radiation. Spectrophotometric assays and Western blot analyses were used to characterize changes in pyruvate dehydrogenase (PDH) activity and function in the heart in response to radiation. Results: Our studies identified myocardial mitochondrial dysfunction as an early event following exposure of heart to radiation. Cardiac irradiation resulted in increased mitochondrial fusion and higher expression of MFN1, a key protein that mediates mitochondrial fusion. The pathological structural and biochemical changes in the myocardial mitochondria are associated with reduced glucose metabolism due to impaired PDH activity. This decline was mediated by increased phosphorylation of PDH in irradiated hearts, which inhibits its activity. Conclusion: Cardiac irradiation results in early metabolic dysregulation, especially in glucose metabolism, which may be exploited for early detection and mitigation of radiation-induced cardiotoxicity. Citation Format: Sarah C. Elliott, Jayesh Sharma, Elizabeth R. Zhang-Velten, Abdallah Elnwasany, Chantal Vidal, Luke Szweda, Prasanna Alluri. Metabolic characterization of radiation-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3209.